CA1274529A - Platinum(ii) complexes of 1,1-cyclobutane- dicarboxylate and process for their production - Google Patents
Platinum(ii) complexes of 1,1-cyclobutane- dicarboxylate and process for their productionInfo
- Publication number
- CA1274529A CA1274529A CA000517055A CA517055A CA1274529A CA 1274529 A CA1274529 A CA 1274529A CA 000517055 A CA000517055 A CA 000517055A CA 517055 A CA517055 A CA 517055A CA 1274529 A CA1274529 A CA 1274529A
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- Prior art keywords
- platinum
- general formula
- cyclobutane
- dicarboxylate
- complexes
- Prior art date
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- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 9
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 13
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 12
- JMXMXKRNIYCNRV-UHFFFAOYSA-N bis(hydroxymethyl)phosphanylmethanol Chemical compound OCP(CO)CO JMXMXKRNIYCNRV-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- UJBFYIXBUHSCOR-UHFFFAOYSA-N 1,2-dichlorocycloocta-1,5-diene;platinum(2+) Chemical compound [Pt+2].ClC1=C(Cl)CCC=CCC1 UJBFYIXBUHSCOR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- JKNZUZCGFROMAZ-UHFFFAOYSA-L [Ag+2].[O-]S([O-])(=O)=O Chemical compound [Ag+2].[O-]S([O-])(=O)=O JKNZUZCGFROMAZ-UHFFFAOYSA-L 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- FWYFVVXZQUGDKK-UHFFFAOYSA-L barium(2+);cyclobutane-1,1-dicarboxylate Chemical compound [Ba+2].[O-]C(=O)C1(C([O-])=O)CCC1 FWYFVVXZQUGDKK-UHFFFAOYSA-L 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- CCQPAEQGAVNNIA-UHFFFAOYSA-L cyclobutane-1,1-dicarboxylate(2-) Chemical compound [O-]C(=O)C1(C([O-])=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-L 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 8
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 229910052788 barium Inorganic materials 0.000 description 4
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 190000008236 Carboplatin Chemical compound 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229910002621 H2PtCl6 Inorganic materials 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 101100285903 Drosophila melanogaster Hsc70-2 gene Proteins 0.000 description 1
- 229910020437 K2PtCl6 Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- -1 platinum (II) com-plexes Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Platinum (II) complexes of 1,1-cyclobutane-dicarbo-xylate having the general formula (I):
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having two carbon atoms at most, and option-ally containing hydroxyl groups, as well as a process for preparing these compounds and a process for preparing the intermediate of formula (II):
Platinum (II) complexes of 1,1-cyclobutane-dicarbo-xylate having the general formula (I):
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having two carbon atoms at most, and option-ally containing hydroxyl groups, as well as a process for preparing these compounds and a process for preparing the intermediate of formula (II):
Description
i27452~3 The present invention relates to platinum (II) com-plexes of l,l-cyclobutane-dicarboxylate of the general formula (I):
R ~ ~ ~ C~ (I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms and optional-ly containing hydroxyl groups,as well as to a process for preparing the same and to a process for preparing the inter-mediate of general formula (II):
R ,Cl Pt (II ~ (II) ¦
R ~ 1 where R=(HO~H2)3P.
The compounds of the present invention are prepared, ln accordance with the scheme below, from respective cis-dichloro platinum (II) bis-substituted intermediates of general formula II as above:
wherein R is as defined for (I):
: .
t~5~3 CiB ~tt )C12~R~2~ ~ SD~A92 ~ ~H20 --(II) cis-[Pt~II)(H20)~lR~ ~ SD4 ~ 2ClAg (III) E a ~0 (IV) R\ Q~~~
Pt(II) ~ ~ S046 F~/ \Q ~ \/ ~ 2H20 (I) The above reactions occur suitably at room tempera-ture in a single step synthesis, and no isolation of inter-mediates of general formula (III) is necessary. The end products thus obtained are isolated by filtration of the formed barium sulphate and subsequent concentration and purification may be achieved by crystallization.
Respective cis-dichloro platinum (II) bis-substituted precurs~rs of general formula (II) are obtained by conventional methods when R is a dialkylsulphide or trialkylphosphine group without hydroxyl groups (Kauffman, GB and Cowan, DO: Inorg.
Synth., (1963) 7, 239-245; Kauffman, GB and Cowan, DO: Ibid, (1960) 6, 211-215; Parshall, GW: Ibid, (1970) 12, 26-33) according to the following reactions:
S~9 Pt ~Cl ~ H2PtCl6 + nitrous gases H2PtCl6 + KCl -~ K2PtC16 + HCl K2PtCl6 + C24K2 K2 4 2CO2 ~ 2KCl r K2PtC14 + 2(H5C2)2 ~tranS-Lptcl2{(Hsc2)2s}2~
[PtC12{(H5C2)}2] + 2(H5C2)2S ~[Pt{(H5C2)2s}4~ C12 ~Pt{(H5C2)2s}4~cl2 ~ cis-[PtC12{(H5C2)2S}2¦ + 2(H5 2)2 K2PtC14 + 2(H5C2)3 [ tC 2{( 5C2)3 }2] 2KCl Applicants have now found out that the preparation of the intermediate of formula (II), wherein R is trishydro-xymethylphosphine {ie R= (HOCH2)3P}, can be suitably carried out by reacting platinum (II) dichloro (1,5-cyclooctadiene) with tris(hydroxymethyl)phosphine in a medium consisting of a solvent selected from low molecular weight alkanols;
methanol and ethanol or their mixtures are preferred.
Applicants have found out that when the preferred methanol and ethanol ratios of between 1:0.8 and 1:1.2 (by volu-me) respectively, are used the reaction occurs advantageously to give a better yield. This finding as well as the fact that the aforesaid intermediate has surprisingly been demonstrated to be an active antitumor compound, accounts for the main purpose of the present invention. This intermediate, chemi-cally known as platinum (II) cis-dichlorobis(trishydroxyme-thylphosphine) has been already described by Chatt, J et al (J.Chem.Soc. (Dalton), 2021-8, 1973) who prepared it by reacting potassium chloroplatinite with tris(hydroxymethyl) phosphine, but did not mention any antitumor activity.
.
, lZ~;t45~9 British Patent No. 1,380,228 discloses, among other com-pounds, cis-diammine (l,l-cyclobutanedicarboxylate)platinum (Carboplatin), which is claimed to possess a remarkable antitumor activity both in man and animals. However, due to the renal toxicity of this compound as-well as a marked emetic action, thus involving a high risk in its human clini-cal use, it was necessary to find other cytostatic analogues having lower renal toxicity and better tolerance.
Applicants have found out that the compounds of general formula (I) and the intermediate of general formula (II), where R= (HOCH2)3P, show significant advantages over Carboplatin with regard to their increased liposolubility and lasting hydrosolubility, thus providing a composition suitable for both oral and injectable administration. There-fore, the compounds of the present invention are useful as a medication in the treatment of tumors and may be administered, mixed with suitable carriers, orally in the form of tablets, capsules, coated-tablets, granules, syrup, solution, etc., or by injection, at daily doses ranging from 10 to 600 mg/m2.
The invention therefore provides a process for pre-paring platinum (II) complexes of l,l-cyclobutane-dicarboxylate of general formula (I):
~O--C
/t(\l) ~ (1) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms, characteriz-ed in that a compound of general formula (II):
cis-¦Pt(II)C12{R}2] (II) , ' .
:
:lZ7~5;29 wherein R is as defined for (I), is reacted with silver sulphate in aqueous dissolution and subsequent reaction with an aqueous dissolution of barium l,l-cyclobutane-dicarboxylate.
The invention also provides platinum (II) complexes of 1,1-cyclobutane-dicarboxylate of general formula (I):
R/ /0 ~C//
/ \O C ~ (I) 10R - ~
wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms whenever prepared according to the above process. The invention further provides a process for preparing an intermediate of general formula (II), where R= (HOCH2)3P, viz:
HOCH2~
CH2 / P\ ~Cl Pt(II) HOCH ~ /
R ~ ~ ~ C~ (I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms and optional-ly containing hydroxyl groups,as well as to a process for preparing the same and to a process for preparing the inter-mediate of general formula (II):
R ,Cl Pt (II ~ (II) ¦
R ~ 1 where R=(HO~H2)3P.
The compounds of the present invention are prepared, ln accordance with the scheme below, from respective cis-dichloro platinum (II) bis-substituted intermediates of general formula II as above:
wherein R is as defined for (I):
: .
t~5~3 CiB ~tt )C12~R~2~ ~ SD~A92 ~ ~H20 --(II) cis-[Pt~II)(H20)~lR~ ~ SD4 ~ 2ClAg (III) E a ~0 (IV) R\ Q~~~
Pt(II) ~ ~ S046 F~/ \Q ~ \/ ~ 2H20 (I) The above reactions occur suitably at room tempera-ture in a single step synthesis, and no isolation of inter-mediates of general formula (III) is necessary. The end products thus obtained are isolated by filtration of the formed barium sulphate and subsequent concentration and purification may be achieved by crystallization.
Respective cis-dichloro platinum (II) bis-substituted precurs~rs of general formula (II) are obtained by conventional methods when R is a dialkylsulphide or trialkylphosphine group without hydroxyl groups (Kauffman, GB and Cowan, DO: Inorg.
Synth., (1963) 7, 239-245; Kauffman, GB and Cowan, DO: Ibid, (1960) 6, 211-215; Parshall, GW: Ibid, (1970) 12, 26-33) according to the following reactions:
S~9 Pt ~Cl ~ H2PtCl6 + nitrous gases H2PtCl6 + KCl -~ K2PtC16 + HCl K2PtCl6 + C24K2 K2 4 2CO2 ~ 2KCl r K2PtC14 + 2(H5C2)2 ~tranS-Lptcl2{(Hsc2)2s}2~
[PtC12{(H5C2)}2] + 2(H5C2)2S ~[Pt{(H5C2)2s}4~ C12 ~Pt{(H5C2)2s}4~cl2 ~ cis-[PtC12{(H5C2)2S}2¦ + 2(H5 2)2 K2PtC14 + 2(H5C2)3 [ tC 2{( 5C2)3 }2] 2KCl Applicants have now found out that the preparation of the intermediate of formula (II), wherein R is trishydro-xymethylphosphine {ie R= (HOCH2)3P}, can be suitably carried out by reacting platinum (II) dichloro (1,5-cyclooctadiene) with tris(hydroxymethyl)phosphine in a medium consisting of a solvent selected from low molecular weight alkanols;
methanol and ethanol or their mixtures are preferred.
Applicants have found out that when the preferred methanol and ethanol ratios of between 1:0.8 and 1:1.2 (by volu-me) respectively, are used the reaction occurs advantageously to give a better yield. This finding as well as the fact that the aforesaid intermediate has surprisingly been demonstrated to be an active antitumor compound, accounts for the main purpose of the present invention. This intermediate, chemi-cally known as platinum (II) cis-dichlorobis(trishydroxyme-thylphosphine) has been already described by Chatt, J et al (J.Chem.Soc. (Dalton), 2021-8, 1973) who prepared it by reacting potassium chloroplatinite with tris(hydroxymethyl) phosphine, but did not mention any antitumor activity.
.
, lZ~;t45~9 British Patent No. 1,380,228 discloses, among other com-pounds, cis-diammine (l,l-cyclobutanedicarboxylate)platinum (Carboplatin), which is claimed to possess a remarkable antitumor activity both in man and animals. However, due to the renal toxicity of this compound as-well as a marked emetic action, thus involving a high risk in its human clini-cal use, it was necessary to find other cytostatic analogues having lower renal toxicity and better tolerance.
Applicants have found out that the compounds of general formula (I) and the intermediate of general formula (II), where R= (HOCH2)3P, show significant advantages over Carboplatin with regard to their increased liposolubility and lasting hydrosolubility, thus providing a composition suitable for both oral and injectable administration. There-fore, the compounds of the present invention are useful as a medication in the treatment of tumors and may be administered, mixed with suitable carriers, orally in the form of tablets, capsules, coated-tablets, granules, syrup, solution, etc., or by injection, at daily doses ranging from 10 to 600 mg/m2.
The invention therefore provides a process for pre-paring platinum (II) complexes of l,l-cyclobutane-dicarboxylate of general formula (I):
~O--C
/t(\l) ~ (1) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms, characteriz-ed in that a compound of general formula (II):
cis-¦Pt(II)C12{R}2] (II) , ' .
:
:lZ7~5;29 wherein R is as defined for (I), is reacted with silver sulphate in aqueous dissolution and subsequent reaction with an aqueous dissolution of barium l,l-cyclobutane-dicarboxylate.
The invention also provides platinum (II) complexes of 1,1-cyclobutane-dicarboxylate of general formula (I):
R/ /0 ~C//
/ \O C ~ (I) 10R - ~
wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms whenever prepared according to the above process. The invention further provides a process for preparing an intermediate of general formula (II), where R= (HOCH2)3P, viz:
HOCH2~
CH2 / P\ ~Cl Pt(II) HOCH ~ /
2 / Cl HOCH2~
wherein platinum (II) dichloro(l,5-cyclooctadiene) is react-ed with tris(hydroxymethyl)phosphine in a medium comprising a solvent selected from low molecular weight alkanols or their mixtures.
The following examples illustrate embodiments of the present invention.
: , lZ~5~
E x a m p 1 e Platinum (II) bis-(diethylsulphide)-l,l-cyclobutane--dicarboxylate as in general formula I, where R= (H5C2)2S
2.00 g (4.48 mmole) of platinum (II) cis-dichloro-bis(diethyl-sulphide), as in general formula II, where R= (H5C2)2S, are added to a solution containing 1.39 g (4.45 mmole) of SO4Ag2 in 200 ml of water. The mixture is stirred for 4 hours under protection from light, filtered off and concentrated to 120 ml.
Barium l,l-cyclobutane-dicarboxylate is prepared by adding 1.41 g (4.47 mmole) of Ba(OH~2. 8H2O to a solution contain-ing 0.74 g (5.13 mmole) or l,l-cyclobutane-dicarboxylic acid in 80 ml of water. Both solutions are mixed up and BaSO4 precipitates. The mixture is then filtered off and concen-trated to give white crystals. By crystallization from acetone, 1.72 g of platinum (II) bis-(diethylsulphide)-l,l-cyclobutane-dicarboxylate as in general formula I, where R= (H5C2)2S, are obtained.
Melting point: 179-180C.
Yield: 74~.
IR Spectrum (KBr), cm : 2980-2940, 1670, 1630, 1330, 1110, 900, 790, 470.
NMR Spectrum (D2O)~: 3.3-2.65(m), 2.1-1.75(m), 3.4(t) J= 7Hz.
f :' ' ~' .
.
~27~5;~9 E x a m p 1 e 2 Platinum (II) bis~(triethylphosphine)~ cyclobu-tane-dicarboxylate as in general formula I, where R= (H5C2)3P, 0.62 g tl.23 mmole) of platinum (II) cis-dichloro-bis-(tri-ethylphosphine) as in general formula II, where R= (H5C2)3P, are added to a solution containing 0.37 g (1.18 mmole) of SO4Ag2 in 50 ml of water. The mixture is stirred for ~
hours under protection from light, filtered off and concentrated to 30 ml. Barium l,l-cyclobutane-dicarboxylate is prepared by adding 0.38 g (1.20 mmole) of Ba(OH). 8H2O to a solution containing 0.2 g (1.38 mmole) of l,l-cyclobutane-dicarboxylic acid in 20 ml of water. Both solutions are mixed up and BaSO4 precipitates. The mixture is then filtered off and concentrated to give white crystals. By crystallization from ethanol, 0.56 g of platinum (II) bis-(triethylphosphine)-l,l-cyclobutane-dicarboxylate of general formula I, where R= (H5C2)3P, are obtained.
Melting point: 201-203C.
Yield: 80~.
IR Spectrum (KBr), cm 1 2960, 2940, 2880, 1650, 1620, 1350, 1115, 1038, 750, 455.
NMR Spectrum (CDC13)¦: 2.85(t) J= 7Hz, 2.1-1.55(m), 1.3-0.95(m).
:' ' ~ , ' ' - ' .' .
',"' '' '' ' ' ' : ' ~2~ 529 E x a m p 1 e 3 Platinum (II) bis-(trishydroxymethylphosphine)-l,l-cyclobutane-dicarboxylate of general formula I, where R= (HOCH2)3P, 1.36 g (2.64 mmole) of platinum ~II) cis-dichloro-bis-(trishydroxymethylphosphine) of general formula II, where R= (HOCH2)3P, are dissolved in 25 ml of water and added to a solution containing 0.82 g (2.63 mmole) of Ag2SO4 in 85 ml Of water. The mixture is then stirred, filtered off and concentrated to 65 ml. Barium l,l-cyclobutane-dicarboxylate is prepared by adding 0.8g g (2.66 mmole) of Ba(OH2). 8H2O
to a solution containing 0.44 g (3.05 mmole) of l,l-cyclo-butane-dicarboxylic acid in 45 ml of water. Both solutions are mixed up and BaSO4 precipitates. The mixture is filtered off and concentrated to near dryness. Absolute ethanol is added and the product is allowed to precipitate. Then, it is filtered again and dried. 1.21 g of platinum (II) bis-(trishydroxymethylphosphine)-l,l-cyclobutane-dicarboxylate of general formula I, where R= (HOCH2)3P, are obtained.
Melting point: 128-132C (d).
Yield: 78%.
IR Spectrum (KBr), cm 1 3600-2700, 1650, 1580, 1400, 1030, 900, 780, 450.
NMR Spectrum (D2O)~ : 4.25(t) J= 24.4Hz; 2.8-2.0(m), 1.9-1.5(m).
.
' . :.
~L27L~L5.~
E x a m p 1 e 4 Platinum (II) cis-dichloro-bis-(trishydroxymethyl)-phosphine ) of general formula II, where R= ~HOCH2)3P, 2.5 g (6.0 mmole) of potassium tetrachloroplatinite (K2PtC14) are dissolved in 40 ml of water and filtered off. The red filtrate, 60 ml of glacial acetic acid and 2.5 ml ~20 mmole) of 1,5-cyclooctadiene are added. The mixture is immediately stirred and heated at nearly 90C in a water bath. After 30minu-tes approximately, the solution, which has become red, slowly becomes light yellow and fine crystals are formed. The dissolution volume is reduced to about 30 ml by underpressure evaporation. Light yellow needles are collected and washed successively with 50 ml of water, ethanol and ether. After drying for 1 hour at 100C, 2.16 g of platinum (II) dichloro(l,5-cyclooctadiene) are obtained which decomposes without melting between 250 and 280C.
4.60 g (12.29 mmole) of platinum (II) dichloro(l,5-cyclooc-tadiene) in 100 ml of ethanol are stirred and added to 3.92 g (31.59 mmole) of 95~ tris(hydroxymethyl)phosphine dissolved in 200 ml of ethanol:methanol (1:3) under a nitrogen atmos-phere. The mixture is stirred until all solid tailings havedissolved, filtered off and concentrated to dryness; then washed with carbon tetrachloride. Finally, the mixture is treated with absolute ethanol to suppress any unreacted phosphine residue. 3.5 ~ of platinum (II) cis-dichloro-bis (tris(hydroxymethyl)phosphine) of general formula II, where R= (HOCH2)3P are obtained.
.
- ~ , ., ~, .
." ' ' ' - - ' . . , ., ~ , . . .
~.2'79~5;29 Melting point: 122-126C.
Yield: 55%.
IR Spectrum (KBr), cm 1 3500_3000, 1360, 1020.
NMR Spectrum ~D2O) ~ : 4.39(t) J= 24~41Hz.
wherein platinum (II) dichloro(l,5-cyclooctadiene) is react-ed with tris(hydroxymethyl)phosphine in a medium comprising a solvent selected from low molecular weight alkanols or their mixtures.
The following examples illustrate embodiments of the present invention.
: , lZ~5~
E x a m p 1 e Platinum (II) bis-(diethylsulphide)-l,l-cyclobutane--dicarboxylate as in general formula I, where R= (H5C2)2S
2.00 g (4.48 mmole) of platinum (II) cis-dichloro-bis(diethyl-sulphide), as in general formula II, where R= (H5C2)2S, are added to a solution containing 1.39 g (4.45 mmole) of SO4Ag2 in 200 ml of water. The mixture is stirred for 4 hours under protection from light, filtered off and concentrated to 120 ml.
Barium l,l-cyclobutane-dicarboxylate is prepared by adding 1.41 g (4.47 mmole) of Ba(OH~2. 8H2O to a solution contain-ing 0.74 g (5.13 mmole) or l,l-cyclobutane-dicarboxylic acid in 80 ml of water. Both solutions are mixed up and BaSO4 precipitates. The mixture is then filtered off and concen-trated to give white crystals. By crystallization from acetone, 1.72 g of platinum (II) bis-(diethylsulphide)-l,l-cyclobutane-dicarboxylate as in general formula I, where R= (H5C2)2S, are obtained.
Melting point: 179-180C.
Yield: 74~.
IR Spectrum (KBr), cm : 2980-2940, 1670, 1630, 1330, 1110, 900, 790, 470.
NMR Spectrum (D2O)~: 3.3-2.65(m), 2.1-1.75(m), 3.4(t) J= 7Hz.
f :' ' ~' .
.
~27~5;~9 E x a m p 1 e 2 Platinum (II) bis~(triethylphosphine)~ cyclobu-tane-dicarboxylate as in general formula I, where R= (H5C2)3P, 0.62 g tl.23 mmole) of platinum (II) cis-dichloro-bis-(tri-ethylphosphine) as in general formula II, where R= (H5C2)3P, are added to a solution containing 0.37 g (1.18 mmole) of SO4Ag2 in 50 ml of water. The mixture is stirred for ~
hours under protection from light, filtered off and concentrated to 30 ml. Barium l,l-cyclobutane-dicarboxylate is prepared by adding 0.38 g (1.20 mmole) of Ba(OH). 8H2O to a solution containing 0.2 g (1.38 mmole) of l,l-cyclobutane-dicarboxylic acid in 20 ml of water. Both solutions are mixed up and BaSO4 precipitates. The mixture is then filtered off and concentrated to give white crystals. By crystallization from ethanol, 0.56 g of platinum (II) bis-(triethylphosphine)-l,l-cyclobutane-dicarboxylate of general formula I, where R= (H5C2)3P, are obtained.
Melting point: 201-203C.
Yield: 80~.
IR Spectrum (KBr), cm 1 2960, 2940, 2880, 1650, 1620, 1350, 1115, 1038, 750, 455.
NMR Spectrum (CDC13)¦: 2.85(t) J= 7Hz, 2.1-1.55(m), 1.3-0.95(m).
:' ' ~ , ' ' - ' .' .
',"' '' '' ' ' ' : ' ~2~ 529 E x a m p 1 e 3 Platinum (II) bis-(trishydroxymethylphosphine)-l,l-cyclobutane-dicarboxylate of general formula I, where R= (HOCH2)3P, 1.36 g (2.64 mmole) of platinum ~II) cis-dichloro-bis-(trishydroxymethylphosphine) of general formula II, where R= (HOCH2)3P, are dissolved in 25 ml of water and added to a solution containing 0.82 g (2.63 mmole) of Ag2SO4 in 85 ml Of water. The mixture is then stirred, filtered off and concentrated to 65 ml. Barium l,l-cyclobutane-dicarboxylate is prepared by adding 0.8g g (2.66 mmole) of Ba(OH2). 8H2O
to a solution containing 0.44 g (3.05 mmole) of l,l-cyclo-butane-dicarboxylic acid in 45 ml of water. Both solutions are mixed up and BaSO4 precipitates. The mixture is filtered off and concentrated to near dryness. Absolute ethanol is added and the product is allowed to precipitate. Then, it is filtered again and dried. 1.21 g of platinum (II) bis-(trishydroxymethylphosphine)-l,l-cyclobutane-dicarboxylate of general formula I, where R= (HOCH2)3P, are obtained.
Melting point: 128-132C (d).
Yield: 78%.
IR Spectrum (KBr), cm 1 3600-2700, 1650, 1580, 1400, 1030, 900, 780, 450.
NMR Spectrum (D2O)~ : 4.25(t) J= 24.4Hz; 2.8-2.0(m), 1.9-1.5(m).
.
' . :.
~L27L~L5.~
E x a m p 1 e 4 Platinum (II) cis-dichloro-bis-(trishydroxymethyl)-phosphine ) of general formula II, where R= ~HOCH2)3P, 2.5 g (6.0 mmole) of potassium tetrachloroplatinite (K2PtC14) are dissolved in 40 ml of water and filtered off. The red filtrate, 60 ml of glacial acetic acid and 2.5 ml ~20 mmole) of 1,5-cyclooctadiene are added. The mixture is immediately stirred and heated at nearly 90C in a water bath. After 30minu-tes approximately, the solution, which has become red, slowly becomes light yellow and fine crystals are formed. The dissolution volume is reduced to about 30 ml by underpressure evaporation. Light yellow needles are collected and washed successively with 50 ml of water, ethanol and ether. After drying for 1 hour at 100C, 2.16 g of platinum (II) dichloro(l,5-cyclooctadiene) are obtained which decomposes without melting between 250 and 280C.
4.60 g (12.29 mmole) of platinum (II) dichloro(l,5-cyclooc-tadiene) in 100 ml of ethanol are stirred and added to 3.92 g (31.59 mmole) of 95~ tris(hydroxymethyl)phosphine dissolved in 200 ml of ethanol:methanol (1:3) under a nitrogen atmos-phere. The mixture is stirred until all solid tailings havedissolved, filtered off and concentrated to dryness; then washed with carbon tetrachloride. Finally, the mixture is treated with absolute ethanol to suppress any unreacted phosphine residue. 3.5 ~ of platinum (II) cis-dichloro-bis (tris(hydroxymethyl)phosphine) of general formula II, where R= (HOCH2)3P are obtained.
.
- ~ , ., ~, .
." ' ' ' - - ' . . , ., ~ , . . .
~.2'79~5;29 Melting point: 122-126C.
Yield: 55%.
IR Spectrum (KBr), cm 1 3500_3000, 1360, 1020.
NMR Spectrum ~D2O) ~ : 4.39(t) J= 24~41Hz.
Claims (13)
1. A process for preparing platinum (II) complexes of 1,1-cyclobutane-dicarboxylate of general formula (I):
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms, characteriz-ed in that a compound of general formula (II):
cis-[Pt(II)C12{R}2] (II) wherein R is as defined for (I), is reacted with silver sulphate in aqueous dissolution and subsequent reaction with an aqueous dissolution of barium 1,1-cyclobutane-dicarboxylate.
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms, characteriz-ed in that a compound of general formula (II):
cis-[Pt(II)C12{R}2] (II) wherein R is as defined for (I), is reacted with silver sulphate in aqueous dissolution and subsequent reaction with an aqueous dissolution of barium 1,1-cyclobutane-dicarboxylate.
2. A process as claimed in claim 1, wherein the alkyl group contains one or more hydroxyl groups.
3. A process as claimed in claim 1, wherein the reaction occurs at room temperature.
4. A process as claimed in claim 2, wherein the reaction occurs at room temperature.
5. A process as claimed in claim 1, wherein the product is obtained by filtration of the formed barium sulphate and subsequent concentration and purification is achieved by crystallisation.
6. A process as claimed in any one of claims 1-3, wherein the product is obtained by filtration of the formed barium sulphate and subsequent concentration and purification is achieved by crystallisation.
7. A process for preparing an intermediate of gene-ral formula (II) as defined in claim 1, where R= (HOCH2)3P, viz:
wherein platinum (II) dichloro(1,5-cyclooctadiene) is reacted with tris(hydroxymethyl)phosphine in a medium comprising a solvent selected from low molecular weight alkanols or their mixtures.
wherein platinum (II) dichloro(1,5-cyclooctadiene) is reacted with tris(hydroxymethyl)phosphine in a medium comprising a solvent selected from low molecular weight alkanols or their mixtures.
8. The process of claim 7, characterized in that the low molecular weight alkanols used as reaction medium are methanol and ethanol.
9. The process of claim 7, wherein the methanol and ethanol are mixed up at the rate of 1:0.8 and 1:1.2 respectively.
10. Platinum(II) complexes of 1,1-cyclobutane-dicar-boxylate of general formula (I):
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms.
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group having at most two carbon atoms.
11. Platinum (II) complexes of 1,1-cyclobutane-dicarboxylate of general formula (I):
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group containing one or more hydroxyl groups having at most two carbon atoms.
(I) wherein R is a dialkylsulphide or trialkylphosphine group, each alkyl group containing one or more hydroxyl groups having at most two carbon atoms.
12. A pharmaceutical composition comprising at least one compound according to claim 10 or 11 in admixture with at least one pharmaceutically acceptable carrier.
13. A composition directed for use in treating tumor diseases comprising at least one compound of general formula (II) where R = (HOCH2)3P as defined in claim 7 together with one or more pharmaceutically acceptable carriers.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES547481A ES8606204A1 (en) | 1985-09-05 | 1985-09-05 | Platinum(ii) complex of 1,1-cyclobutanedicarboxylate, manufacture, manufacture of cis-dichloro platinum(ii) bis-substituted intermediate and medicine composition |
| ES547,481 | 1985-09-09 | ||
| ES548849A ES8702398A2 (en) | 1985-10-23 | 1985-10-23 | Improvements in the object of Patent No. 547,481 relating to PROCEDURE FOR OBTAINING NEW PLATINUM(II) COMPLEXES DERIVED FROM 1,1-CYCLOBUTANEDICARBOXYLATE |
| ES548,849 | 1985-10-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1274529A true CA1274529A (en) | 1990-09-25 |
Family
ID=26156122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000517055A Expired - Fee Related CA1274529A (en) | 1985-09-05 | 1986-08-13 | Platinum(ii) complexes of 1,1-cyclobutane- dicarboxylate and process for their production |
Country Status (4)
| Country | Link |
|---|---|
| EP (2) | EP0302181B1 (en) |
| CA (1) | CA1274529A (en) |
| DE (2) | DE3679199D1 (en) |
| PH (1) | PH22215A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2000614A6 (en) * | 1986-08-04 | 1988-03-01 | Ferrer Int | Complexes of platinum (II) 2,3-dinitrilo-2-butene-2,3-dithiolate, a process for preparing them and pharmaceutical compositions containing them. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH588505A5 (en) * | 1972-06-08 | 1977-06-15 | Research Corp | |
| GB8328218D0 (en) * | 1983-10-21 | 1983-11-23 | Johnson Matthey Plc | Oral compositions |
-
1986
- 1986-08-13 CA CA000517055A patent/CA1274529A/en not_active Expired - Fee Related
- 1986-09-01 PH PH34206A patent/PH22215A/en unknown
- 1986-09-05 EP EP88106222A patent/EP0302181B1/en not_active Expired - Lifetime
- 1986-09-05 DE DE8888106222T patent/DE3679199D1/en not_active Expired - Fee Related
- 1986-09-05 DE DE8686112285T patent/DE3675859D1/en not_active Expired - Fee Related
- 1986-09-05 EP EP86112285A patent/EP0215393B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0302181A2 (en) | 1989-02-08 |
| EP0215393A3 (en) | 1988-03-30 |
| EP0215393A2 (en) | 1987-03-25 |
| DE3679199D1 (en) | 1991-06-13 |
| DE3675859D1 (en) | 1991-01-10 |
| EP0302181A3 (en) | 1989-03-08 |
| EP0302181B1 (en) | 1991-05-08 |
| EP0215393B1 (en) | 1990-11-28 |
| PH22215A (en) | 1988-06-28 |
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